Summary of Work: Interspersed repetitive sequences are an important class of at-risk motifs (ARMs) that can lead to human genome instability. Using the yeast Saccharomyces cerevisiae, we are investigating mechanisms of genomic instability caused by human ARMS. The one million Alu elements in the human genome are a major class of repetitive DNA, where the average Alu homology is 85% and Alus frequently appear as inverted repeats (IRs). We showed in yeast and mouse cells that IRs can induce recombination, suggesting that they are sources of rearrangements. We therefore determined if inverted Alu repeats (which are ~300 bp) are contributors to genomic change in humans. We developed a yeast-based recombination system to address the role of sequence divergence, distance between repeats and genetic background on the ability of an inverted pair of Alu repeats to induce genetic instability. We found that inverted Alu repeats which are more than 85% identical and separated by <20 bp are highly efficient at stimulating mitotic recombination. The instability is due to double-strand breaks and the repair of these breaks depends on the Mre11/Rad50/Xrs2 complex and Sae2 protein. The repair requirements are novel compared to other types of DSBs. Compariing breaks generated by inverted Alu repeats and breaks made by I-Sce endonuclease revealed a requirement for the meiotic-specific functions of the Mre11/Rad50/Xrs2 complex and Sae2 protein in processing the mitotic breaks. The breaks lead to chromosomal inversions and a model has been derived that generally explains inversions. Based on the yeast results, we did a computational analysis of the human genome and developed a website for the Alu analysis. As predicted from yeast, we found that closely spaced, highly homologous inverted Alus in contrast to direct Alu repeats are rare in human genome. Based on parameters for unstable inverted Alus identified in yeast, loci were identified in the human genome that might have potential for rearrangements in normal or mutant cells